Understanding the role of host factors during lethal influenza virus infection is critical to deciphering the events that will determine the fate of the host. One such factor is encoded by the Mx1 gene, which confers resistance to influenza virus infection. Here, we compared pathology and global gene expression profiles in lung tissue from BALB/c (Mx1(-)) and BALB·A2G-Mx1 mice (Mx1(+/+)) infected with the fully reconstructed 1918 pandemic influenza virus. Mx1(+/+) mice showed less tissue damage than Mx(-) animals, and pathology and mortality were further reduced by treating the mice with interferon prior to infection. Using global transcriptional profiling, we identified distinct molecular signatures associated with partial protection, complete protection, and the contribution of interferon to the host response. In the absence of interferon treatment, partial protection was characterized by the generation of an acute response with the up-regulation of genes associated with apoptosis, reactive oxygen species, and cell migration. Complete protection was characterized by the down-regulation of cytokine and chemokine genes previously associated with influenza virus pathogenesis. The contribution of interferon treatment to total protection in virus-infected Mx1(+/+) mice was characterized by the altered regulation of cell-cycle genes. These genes were up-regulated in Mx1(+/+) mice treated with interferon but down-regulated in the absence of interferon treatment. Our results suggest that Mx1(+/+) mice generate a protective antiviral response by controlling the expression of key modulator molecules associated with influenza virus lethality.